Doxorubicin (adriamycin) is widely used as an antitumor agent in the treatment of a wide range of solid tumors and leukemias. However, many patients with these tumors fail to respond and essentially no patients with some serious tumor types (colon cancer, melanoma) respond. In addition, in some patients chronic treatment produces irreversible heart damage that can be fatal if treatment is continued. Thus, there is continuing need for analogs which give a better rate of response, a wider spectrum of response, or reduced cardiotoxicity. Various analogs have been screened in a widely used test against mouse leukemia P388 and most have been found wanting. Others are useful, but do not provide a complete solution to the problem.
Much of the history and prior art of doxorubicin and its anthracycline analogs is found in the article "Adriamycin" by David W. Henry, ACS Symposium Series, No. 30, Cancer Chemotherapy, American Chemical Society, pp. 15-57 (1976) and in the book Doxorubicin By Frederico Arcamone, Acadamic Press, 1981.
Some specific analogs are of interest. N,N-dibenzyl-daunorubicin is disclosed in U.S. Pat. No. 4,035,566 (1977); 5-iminodaunorubicin in U.S. Pat. No. 4,109,076 (1978); the doxorubicin equivalent in E. Acton et al, J Med Chem (1981) 24: 669; and 3'-deamino-3'-(4-morpholinyl) daunorubicin in U.S. Pat. No. 4,301,277 (1981).
A general reductive alkylation process for preparing new semisynthetic anthracycline derivatives is described in Tong, G. L., et al, J Med Chem (1979) 22: 912-918. Piperidinyl and 4-methoxypiperidinyl derivatives are disclosed in U.S. Pat. Nos. 4,202,967 (1980) and 4,314,054 (1982). Cyanmorpholino analogs are disclosed in U.S. Pat. No. 4,464,529 (1984).
A group of bridged oxygen analogs was disclosed in U.S. Ser. No. 598,016, of which this is a continuation in part. The present application discloses further details related to a subclass of this group, the 4-alkoxy piperidinyl derivatives. The morpholino analogs are also described in Acton, E. M., et al, J Med Chem (1984) 27: 638.
The subject matter of this prior art is specifically incorporated herein by reference.